CN100478688C - Reactive chip and method for detecting bond of target substance using that chip - Google Patents
Reactive chip and method for detecting bond of target substance using that chip Download PDFInfo
- Publication number
- CN100478688C CN100478688C CNB2004800019163A CN200480001916A CN100478688C CN 100478688 C CN100478688 C CN 100478688C CN B2004800019163 A CNB2004800019163 A CN B2004800019163A CN 200480001916 A CN200480001916 A CN 200480001916A CN 100478688 C CN100478688 C CN 100478688C
- Authority
- CN
- China
- Prior art keywords
- capture probe
- vibration plane
- vibration
- target substance
- reactive chip
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Expired - Fee Related
Links
Images
Classifications
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
- G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
- G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
- G01N33/543—Immunoassay; Biospecific binding assay; Materials therefor with an insoluble carrier for immobilising immunochemicals
- G01N33/54366—Apparatus specially adapted for solid-phase testing
- G01N33/54373—Apparatus specially adapted for solid-phase testing involving physiochemical end-point determination, e.g. wave-guides, FETS, gratings
- G01N33/5438—Electrodes
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/00583—Features relative to the processes being carried out
- B01J2219/00603—Making arrays on substantially continuous surfaces
- B01J2219/00605—Making arrays on substantially continuous surfaces the compounds being directly bound or immobilised to solid supports
- B01J2219/00632—Introduction of reactive groups to the surface
- B01J2219/00637—Introduction of reactive groups to the surface by coating it with another layer
-
- B—PERFORMING OPERATIONS; TRANSPORTING
- B01—PHYSICAL OR CHEMICAL PROCESSES OR APPARATUS IN GENERAL
- B01J—CHEMICAL OR PHYSICAL PROCESSES, e.g. CATALYSIS OR COLLOID CHEMISTRY; THEIR RELEVANT APPARATUS
- B01J2219/00—Chemical, physical or physico-chemical processes in general; Their relevant apparatus
- B01J2219/00274—Sequential or parallel reactions; Apparatus and devices for combinatorial chemistry or for making arrays; Chemical library technology
- B01J2219/0068—Means for controlling the apparatus of the process
- B01J2219/00702—Processes involving means for analysing and characterising the products
- B01J2219/00704—Processes involving means for analysing and characterising the products integrated with the reactor apparatus
Abstract
A novel chip capable of reducing a reaction period, applying wide-ranging target substance, preventing a mismatch binding efficiently and enabling a highly accurate detection is provided. Thus, an inventive reactive chip has the capture probe (60) fixed on each of three or more vibration areas (50) arranged on the support (30), the capture probes being able to binding to a target substance, wherein each vibration area has the vibration-generating part (40) having the first electrode (11) and the second electrode (12) between which the piezoelectric/electrostrictive element (20) is sandwiched.
Description
Technical field
The present invention relates to reactive chip and the detection method of utilizing the target substance of this chip.In more detail, relate to new reactive chip and the new detection method of utilizing the target substance of this chip, it can get rid of the mistake hybridization of target substance and capture probe, and can carry out correct detection at short notice, can also select various detection methods and object.
Background technology
Be intended to gene structure and gene expression ways is carried out in a large number and resolve fast, used various reactive chips.This reactive chip constitutes, with thousands of and even tens thousand of above different capture probes as point and permutation is fixed on the substrate such as glass sheet, with the target substance crossed by signs such as fluorescence and capture probe combine have or not as index, can carry out quantitatively the amount of specific target substance or the target substance in the sample.Be fixed on capture probe on the chip according to the kind of target substance to be resolved and different.For example, become the situation of target substance at DNA, RNA, employing can be with it complementary in conjunction with (hybridization) two strands or single stranded DNA fragment, polynucleotide chain, oligonucleotide chain etc. as capture probe, they be called as DNA chip (or DNA array) (reference example as, patent documentation 1-4, non-patent literature 1,2).Also have, under the situation of protein-chip, protein or peptide bond, and with the acceptor or the antibody of their specific bond, constitute the relation of target substance-capture probe.
The combination of the target substance on reactive chip, for example: the test portion (sample solution) that contains the signization target substance is contacted with reactive chip, reaction a period of time, make target substance and capture probe combination, after removing unconjugated material, by the home position on the detection reaction chip, judge target substance and which capture probe combination.In addition, by measuring the intensity of id signal, also can the quantitative objective amount of substance.
Reactive chip in the past passes through freely to spread and the approaching also combination of corresponding capture probe in order to make the target substance in the sample solution, and sample solution and reactive chip is reacted for a long time.So, exist to obtain till the testing result, need problem for a long time.
Also have, the precision of utilizing reactive chip that target substance is detected depends on target substance and combines with the specificity of capture probe.The situation of DNA chip for example, target dna and dna probe are complementary fully mutually in conjunction with being desirable, but in fact by several mispairing, target dna also may be incorporated into dna probe.Especially, with under the situation of mode near dna probe that freely spreads, this mispairing is greatly dangerous in conjunction with (mistake hybridization) in sample solution for target dna.
As the DNA chip that addresses this is that, the known invention (nano chips) that has in the patent documentation 5.This nano chips are stationary probe DNA on electrode surface, and under the situation of giving the logical positive direct-current electric current of this electrode, make the hybridization of target dna and dna probe.Because dna fragmentation (target dna) is electronegative, can the approaching and combination with positively charged dna probe at short notice.After hybridization reaction finishes, to the logical negative DC current of electrode.Like this, dna probe and target dna all become electronegative state, will be repelled by dna probe with the target dna of dna probe mispairing, on dna probe only remaining by correct complementation the target dna of combination.
But, because these this nano chips have utilized DNA electronegative character usually, so be not suitable on the protein-chip of protein or peptide.
List of references
Patent documentation 1: United States Patent (USP) the 5th, 474, No. 796 instructionss
Patent documentation 2: United States Patent (USP) the 5th, 605, No. 662 instructionss
Patent documentation 3: the international pamphlet that discloses No. 95/251116
Patent documentation 4: the international pamphlet that discloses No. 95/35505
Patent documentation 5: special table 2001-501301 communique
Non-patent literature 1:Schena, M.et al., Proc.Natl.Acad.Sci.USA.93:10614-10619,1996.
Non-patent literature 2:Heller, R.A.et al., Proc.Natl.Acad.Sci.USA.94:2150-21551997.
Summary of the invention
The application's invention is carried out in view of above situation, and its purpose is, provides at target substance widely, can shorten the reaction time, can prevent effectively mispairing in conjunction with, obtain high-precision test result's new reactive chip.
And the another purpose of the application's invention is, the new detection method of the target substance that has used above-mentioned reactive chip is provided.
The application's the 1st invention is a reactive chip, it is characterized in that: arranged the vibration plane more than 3 or 3 in permutation on the substrate, and be fixed with the capture probe that combines with target substance on each vibration plane.
The 2nd invention is a kind of form of described the 1st invention, and it is that each vibration plane has the reactive chip that inserts the vibration generating unit of piezoelectric/electrostrictive film element between the 1st electrode and the 2nd electrode respectively.
The 3rd invention is a kind of form of described the 2nd invention, is the reactive chip of the stationary plane of capture probe through the bag quilt.
The 4th invention is a kind of form of the described the 2nd or the 3rd invention, be that substrate has thin-wall regions and the thick wall area around it, and there is the reactive chip of vibration generating unit the thin-wall regions top.
The 5th invention is the another kind of form of the described the 2nd or the 3rd invention, be that substrate has thin-wall regions and the thick wall area around it, and there is the reactive chip of vibration generating unit the thin-wall regions below.
The 6th invention is a kind of form of described the 2nd to the 5th invention, is that the lead-in wire separately of the 1st electrode and the 2nd electrode is a reactive chip independently for each vibration generating unit.
The 7th invention is the another kind of form of described the 2nd to the 5th invention, and the lead-in wire that is any one party in the 1st electrode and the 2nd electrode is shared reactive chip.
The 8th invention is a kind of form of described the 2nd to the 7th invention, is the reactive chip with unit of the resonant frequency of measuring piezoelectric/electrostrictive film element.
The 9th invention is the another kind of form of described the 2nd to the 7th invention, is that the 1st electrode surface is the stationary plane of capture probe, except that AC power, and then has also connected the reactive chip of direct supply at the 1st electrode and the 2nd electrode.
The 10th invention is other form of another kind of described the 2nd to the 7th invention, is the reactive chip that is fixed with various different types of capture probes at each vibration plane.
The 11st invention is a kind of form of described the 10th invention, is the reactive chip with resonant frequency unit of measuring piezoelectric/electrostrictive film element.
The 12nd invention is the another kind of form of described the 10th invention, is that the 1st electrode surface is the stationary plane of capture probe, and the 1st electrode and the 2nd electrode and then have also been connected the reactive chip of direct supply except that AC power.
The 13rd invention is the described the 2nd to the 7th invention and then another kind of form, vibration plane permutation more than 3 or 3 is arranged to same row or the vibration plane permutation more than 4 or 4 is arranged to the clathrate of n (n is more than or equal to 2) * m (m is more than or equal to 2), and on each vibration plane of same row, be fixed with reactive chip with a kind of capture probe.
The 14th invention is a kind of form of described the 13rd invention, is the reactive chip with unit of the resonant frequency of measuring piezoelectric/electrostrictive film element.
The 15th invention is the another kind of form of described the 13rd invention, is that the 1st electrode surface is the stationary plane of capture probe, and the 1st electrode and the 2nd electrode and then have also been connected the reactive chip of direct supply except that AC power.
The 16th invention is the 2nd to the 7th invention and then another kind of form, vibration plane permutation more than 3 or 3 is arranged to same row or the vibration plane permutation more than 4 or 4 is arranged to the clathrate of n (n is more than or equal to 2) * m (m is more than or equal to 2), and on the vibration plane of same row, be fixed with the reactive chip of the capture probe that combines with the target substance different parts respectively.
The 17th invention is a kind of form of described the 16th invention, is the reactive chip with unit of the resonant frequency of measuring piezoelectric/electrostrictive film element.
The 18th invention is the another kind of form of described the 16th invention, is that the 1st electrode surface is the stationary plane of capture probe, and the 1st electrode and the 2nd electrode and then have also been connected the reactive chip of direct supply except that AC power.
The 19th invention is the method that detects the target substance that combines with capture probe, it is characterized in that, under the state of the vibration plane vibration that makes the described the 10th reactive chip of inventing, the test portion that contains the signization target substance is contacted with the capture probe of reactive chip, stop the vibration of vibration plane, as index, detect the target substance that is incorporated into capture probe with sign.
The 20th invention is a kind of form of the 19th invention, is when making vibration plane vibration, make temperature through the time state that changes under, the detection method that test portion is contacted with capture probe.
The 21st invention is the method that detects the target substance that combines with capture probe, it is characterized in that, under the state of the vibration plane vibration that makes the described the 11st reactive chip of inventing, the test portion that contains target substance is contacted with the capture probe of reactive chip, as index, detect target substance with the variation of the resonant frequency of piezoelectric/electrostrictive film element.
The 22nd invention is a kind of form of described 21 inventions, be in the vibration plane vibration that makes reactive chip, make temperature through the time state that changes under, probe is contacted with test portion, with the variation of the resonant frequency of piezoelectric/electrostrictive film element as index, through the time detect the detection method of target substance.
The 23rd invention is the method that detects the target substance that combines with capture probe, it is characterized in that, under the state of the vibration plane vibration that makes the described the 12nd reactive chip of inventing, the test portion that contains the signization target substance and the probe of reactive chip are contacted, after waiting to stop the vibration of vibration plane, give the negative direct current of connecting certain hour as the 1st electrode of the stationary plane of capture probe, detect the target substance that is incorporated into capture probe as index with sign.
The 24th invention is to detect the method for multiple target substance to the compatibility of capture probe, the method of this detection target substance is characterised in that, under the state of each vibration plane with different amplitude vibrations of the same row vibration plane that makes the described the 13rd reactive chip of inventing, multiple sign target substance is contacted with the capture probe of reactive chip, stop the vibration of vibration plane, detect the compatibility degree of the target substance of capture probe that be incorporated into as index each probe with sign.
The 25th invention is a kind of form of described the 24th invention, is when making vibration plane vibration, make temperature through the time state that changes under, the detection method that test portion is contacted with capture probe.
The 26th invention is to detect the method for multiple target substance to the compatibility of capture probe, the method of this detection target substance is characterised in that, under the state of same row vibration plane with different amplitude vibrations of the reactive chip that makes described the 14th invention, target substance is contacted with the capture probe of reactive chip, as index, detect the compatibility degree of target substance with the variation of the resonant frequency of piezoelectric/electrostrictive film element to each capture probe.
The 27th invention is a kind of form of described the 26th invention, be in the vibration plane vibration that makes reactive chip, make temperature through the time state that changes under, test portion is contacted with capture probe, with the variation of the resonant frequency of piezoelectric/electrostrictive film element as index, through the time detect the detection method that has or not of target substance.
The 28th invention is to detect the method for plurality of target material to the compatibility of capture probe, the method of this detection target substance is characterised in that, under the state of same row vibration plane with different amplitude vibrations of the reactive chip that makes described the 15th invention, various sign target substances are contacted with the capture probe of reactive chip, after waiting to stop the vibration of vibration plane, give the negative DC current of connecting certain hour as the 1st electrode of the stationary plane of capture probe, detect the compatibility degree of the target substance of capture probe that be incorporated into as index each probe with sign.
The 29th invention is the method that detects the target substance variation, it is characterized in that, under the situation of the same row vibration plane vibration that makes the described the 16th reactive chip of inventing, the test portion that contains the signization target substance is contacted with the capture probe of reactive chip, stop the vibration of vibration plane, by detecting the target substance that is incorporated into capture probe as index, detect the variation of target substance with sign.
The 30th invention is the method that detects the target substance variation, it is characterized in that, under the situation of the same row vibration plane vibration that makes the described the 17th reactive chip of inventing, the test portion that contains target substance is contacted with the capture probe of reactive chip, by with the variation of the resonant frequency of piezoelectric/electrostrictive film element as index, detect having or not of target substance, detect the variation of target substance.
The 31st invention is the method that detects the target substance variation, the detection method of this target substance is characterised in that, under the situation of the same row vibration plane vibration that makes the described the 18th reactive chip of inventing, the test portion that contains the signization target substance is contacted with the capture probe of reactive chip, after waiting to stop the vibration of vibration plane, give the negative DC current of connecting certain hour as the 1st electrode of the stationary plane of capture probe, by with the sign as index, detection is incorporated into the target substance of capture probe, detects the variation of target substance.
Description of drawings
Fig. 1 is the outboard profile of basic structure one example of expression reactive chip of the present invention.
Fig. 2 is another routine outboard profile of basic structure of expression reactive chip of the present invention.
Fig. 3 is the outboard profile of another example of the basic structure of expression reactive chip of the present invention.
Fig. 4 is the outboard profile of an embodiment of expression reactive chip of the present invention.
Fig. 5 is the outboard profile of another embodiment of expression reactive chip of the present invention.
Fig. 6 is the outboard profile of another embodiment of expression reactive chip of the present invention.
Fig. 7 is reactive chip of the present invention and then planimetric map another embodiment and an outboard profile of expression.
Fig. 8 is the reactive chip of the present invention and then planimetric map another embodiment of expression.
Fig. 9 is the mode chart of the arrangement example of the capture probe in the expression reactive chip of the present invention, and square is represented vibration plane, the difference of different letter representation capture probes.
Figure 10 is the mode chart of another arrangement example of the capture probe in the expression reactive chip of the present invention, and square is represented vibration plane, the difference of different letter representation capture probes.
Figure 11 is the mode chart (right side) that the capture probe of expression in the reactive chip of the present invention another arranged the mode chart (left side) of example and the illustration bonding state of normal dyeing body when utilizing this reactive chip detection chromosome abnormality etc.; Square is represented vibration plane, and the horizontal wave-like line that runs through vibration plane is represented oscillator, the difference of different letters and different numeral capture probes.
Figure 12 is capture probe and then the another mode chart of arranging example in the expression reactive chip of the present invention, and square is represented vibration plane, the difference of different letters and different numeral capture probes.
Figure 13 is the arrangement example (left side) of illustrative capture probe among Figure 11 and the mode chart (right side) of illustrative bonding state when utilizing this reactive chip to detect chromosome abnormality (insertion); Square is represented vibration plane, and the horizontal wave-like line that runs through vibration plane is represented oscillator, the difference of different letters and different numeral capture probes.
Figure 14 is the arrangement example (left side) of illustrative capture probe among Figure 11 and the mode chart (right side) of illustrative bonding state when utilizing this reactive chip to detect chromosome abnormality (disappearance); Square is represented vibration plane, and the horizontal wave-like line that runs through vibration plane is represented oscillator, the difference of different letters and different numeral capture probes.
Figure 15 is the arrangement example (left side) of illustrative capture probe among Figure 12 and the mode chart (right side) of illustrative bonding state when utilizing this reactive chip to detect chromosome abnormality (insertion); Square is represented vibration plane, and the horizontal wave-like line that runs through vibration plane is represented oscillator, the difference of different letters and different numeral capture probes.
Figure 16 is the arrangement example (left side) of illustrative capture probe among Figure 12 and the mode chart (right side) of illustrative bonding state when utilizing this reactive chip to detect chromosome abnormality (replacement); Square is represented vibration plane, and the horizontal wave-like line that runs through vibration plane is represented oscillator, the difference of different letters and different numeral capture probes.
Wherein,
11 the 1st electrodes
12 the 2nd electrodes
13,14 lead-in wires
20 piezoelectric/electrostrictive film elements
30 substrates
31 thin-wall regions
32 thick wall area
40 vibration generating units
50 vibration planes
60 capture probes
70 bag tegillums
Embodiment
The application's the 1st invention is a reactive chip, it is characterized in that, has arranged the vibration plane more than 3 or 3 in permutation on the substrate, and fixed the capture probe that combines with target substance on each vibration plane.
" substrate " is resin plate, sheet metals etc. such as the glass sheet that is used in DNA chip, protein-chip etc. usually, ceramic wafer, plastics." capture probe " is the biomolecule with the target substance specific bond.For example: when target substance is the dna fragmentation (for example cDNA etc.) in genome source, capture probe be based on complementarity and with the single stranded DNA fragment of these dna fragmentations hybridization, RNA fragment, nucleotide chain (100 bases or its above polynucleotide chain or the oligonucleotides of 100 bases of less than) etc.Also have, when target substance is protein, capture probe can be can with the protein (for example receptor protein) of a part of specific bond of the amino acid sequence of target substance, peptide etc., perhaps with the antibody of the antigenic determinant specific bond of protein or its Fab, F (ab ')
2, Fv fragment etc.In addition, the microorganism such as compound bio molecule, biological tissue's sheet, cell, yeast with sugar chain also can be used as capture probe.
These capture probes can be the same with DNA chip, protein-chip in the past, is arranged on the substrate with known method.Such as the situation of DNA chip, can adopt method, dna fragmentation is fixed to method on the substrate according to the point sample method at synthetic DNA fragment on the substrate (for example about 25mer).The point sample method preferably adopts and is documented in that the spy opens the 2001-116750 communique, the spy opens the specking method in the 2001-186881 communique.After point sample finishes, the same with the manufacturing of common reactive chip, by sampling point interpolation moisture (keeping certain hour about humidity～80%), high temperature drying combination, soup are handled and carried out immobilization processing etc., each sampling point is fixed on the substrate.And then, in manufacturing, can also carry out opening overlapping point sample in the 2001-186880 communique as being documented in the spy according to the reactive chip of point sample method.When fixing protein, peptide, tissue, cell etc., biologic specificity adsorbent, organic polymer etc. can be wrapped in advance by in stationary plane, capture probe is fixed on this bag tegillum then.
Capture probe in the reactive chip of the 1st invention is fixed on the vibration plane more than 3 or 3 separately.Each " vibration plane " can keep at interval being arranged on the substrate apart from permutation about 100～1000 μ m, is circular about 50～500 μ m or is rectangle about 50～500 μ m Yi Bian the size of each vibration plane is a diameter.This vibration plane is with specific frequency, the face of amplitude vibration.Such vibration plane for example can be made by suitable vibration generating arrangement (for example electromagnet, low frequency generating means) is set below the probe stationary face of substrate, but among the application, the structure of preferred the 2nd invention.
The 2nd invention is the reactive chip that each vibration plane has the vibration section that the insertion piezoelectric/electrostrictive film element forms between the 1st electrode and the 2nd electrode separately.Vibration plane in this case can be a structure as described in Figure 1.That is, in the example of Fig. 1, between the 1st electrode (11) and the 2nd electrode (12), insert piezoelectric/electrostrictive film element (20) and constitute vibration generating unit (40), and should vibrate that generating unit (40) is fixed on the substrate (30) and formation vibration plane (50).Add alternating voltage when the 1st electrode (11) and the 2nd electrode (12), piezoelectric/electrostrictive film element (20) along with the frequency of voltage to arrow directions X continuous and adjustable, but this moment, consequently, vibration plane (50) vibrated to arrow Y direction because substrate (30) is not flexible.The cycle of vibration is along with electric voltage frequency, amplitude change along with voltage swing.The relation of the 1st electrode (11), the 2nd electrode (12), piezoelectric/electrostrictive film element can also be arranged to as Fig. 2 and Fig. 3.In the example of Fig. 2, arranged the 1st electrode (11) up and down, between piezoelectric/electrostrictive film element, inserted the 2nd electrode (12) at piezoelectric/electrostrictive film element (20).In this structure, along with the flexible increase of piezoelectric/electrostrictive film element (20) to directions X, the vibratory output of Y direction also increases.In the example of Fig. 3, the 1st electrode (11) and the 2nd electrode (12) subtend of comb type is placed in parallel on the substrate (30), and arranges piezoelectric/electrostrictive film element (20) betwixt.In this case, the vertical effect flexible owing to the electric field induction that has utilized piezoelectric/electrostrictive film element (20) obtains the vibration of Y direction, so can be vibrated fully with less voltage.
Piezoelectric/electrostrictive film element (20) is known piezoelectric/electrostrictive film element or anti-iron dielectric.Such as the pottery that can adopt lead zirconates, lead titanates, magnesium lead niobate, nickel lead niobate, zinc niobate lead, manganese lead niobate, antimony lead stannate, manganese lead tungstate, cobalt lead niobate, barium titanate etc. separately or adopt contain these combination in any and the pottery of composition.Particularly suitable the use with the composition of lead zirconates, lead titanates and magnesium lead niobate formation material as principal ingredient.Reason is, this material except that having high electricapparatus attachment coefficient and piezoelectric constant, reactive little with substrate (30) in the sintering of piezoelectric/electrostrictive film element (20), the material that formation regulation that can be stable is formed.
Further, can also utilize the oxide that in above-mentioned pottery, suitably adds lanthanum, calcium, strontium, molybdenum, tungsten, barium, niobium, zinc, nickel, manganese, cerium, chromium, cobalt, antimony, iron, yttrium, tantalum, lithium, bismuth, tin etc., or these combination in any, or other compounds and the pottery that obtains.For example, the preferred use with lead zirconates, lead titanates and magnesium lead niobate is principal ingredient, the pottery that contains lanthanum, strontium therein, and then added the pottery of manganese, because the mechanical quality coefficient (Q value) of piezoelectric is big, not only on the structure of reactive chip, can also can increase the Q value from the material aspect, be preferred.
The 1st electrode (11) and the 2nd electrode (12) are preferably by at room temperature constituting for the conductive metal of solid.For example, can use with metal monomer such as aluminium, titanium, chromium, iron, cobalt, nickel, copper, zinc, niobium, molybdenum, ruthenium, palladium, rhodium, silver, tin, tantalum, tungsten, iridium, platinum, gold, lead or these combination in any and alloy.Further, can also use in these metals disperse with piezoelectric/electrostrictive film element (20) or substrate (30) identical materials and cermet material.
Utilize above material to form in the situation of vibration generating unit (40) and vibration plane (50), for example, if the structure of Fig. 1, then after substrate (30) is gone up formation the 2nd electrode (12), on the 2nd electrode (12), burn till piezoelectric/electrostrictive film element (20), form the 1st electrode (11) at last.Perhaps the 1st electrode (11), the 2nd electrode (12) and piezoelectric/electrostrictive film element (20) integral body can also be burnt till at substrate (30) and go up and form.The shaping of this vibration plane that burns till according to integral body, under the situation of the structure of Fig. 2, Fig. 3, particularly preferred.
The 1st electrode (11), the 2nd electrode (12) and separately lead-in wire contact with target substance can carry out everywhere insulation-coated.As this lining material, can use insulativity glass or resin.As resin, for example can use the good fluororesin of chemical stability, for example tetrafluoroethylene resin class teflon (polytetrafluoroethylene PTFE that Co., Ltd. of Du Pont's (デ ユ Port Application) makes), tetrafluoraoethylene-hexafluoropropylene copolymer resene teflon (teflon FEP), tetrafluoroethene-perfluoroalkyl vinyl ether copolymer resin class teflon (teflon PFA), PTFE/PFA ptfe composite etc.Also have, silicones (preferably thermohardening type silicones), epoxy resin, acryl resin etc. also can use according to purpose.And then preferably add the rigidity that inorganic organic compaction material is adjusted vibration plane (50) to insulative resin.
If the thickness of vibration plane (50) is reduced, for example in measuring, resonant frequency described later can improve sensitivity, but produce degradation problem under the rigidity but then, so be preferably 5～50 μ m by the thickness total of substrate (30) and the vibration plane (50) formed of vibration generating unit (40).
Fig. 4 is the side cross-sectional view of an embodiment of expression the 2nd invention reactive chip.Illustrative reactive chip is surperficial with the 2nd electrode (12), piezoelectric/electrostrictive film element (20), the stacked integrated formation of the 1st electrode (11) at substrate (30) in this Fig. 4.And the surface of the 1st electrode (11) is provided with capture probe (60).Capture probe (60) can be as shown in the example of Fig. 4, directly be fixed on the surface of vibration generating unit (40), or as shown in the example of Fig. 5, bag is fixed on capture probe (60) this bag tegillum (70) then and goes up (the 3rd invention) by the surface of vibration generating unit (40) earlier.This bag tegillum (70) is for being easy to the material of immobilized capture probes (60), kind according to capture probe (60), for example can from, silane such as polynucleotide L ricin layer, gamma-aminopropyl-triethoxy-silane with and organic polymers such as biospecific adsorbent, polyacrylamide, nylon membrane such as derivant, biotin/avidin etc. in suitably select.
In the example of Fig. 4 and Fig. 5, substrate (30) has thin-wall regions (31) and the thick wall area (32) around it, and thin-wall regions (31) forms, and has vibration generating unit (40) in the above and formation vibration plane (50) (the 4th invention).By this thin-wall regions (31) and thick wall area (32) are set, can keep the reactive chip whole rigidity, and make vibration plane (50) that suitable vibration take place.This thin-wall regions (31) and thick wall area (32) can also be as Fig. 6 be illustrative, the lower end of extension thick wall area (32) and make the following formation of thin-wall regions (31) empty.Such structure can improve substrate (30) whole rigidity, thereby preferred.
In addition, reactive chip of the present invention can also will vibrate the below (the 5th invention) that generating unit (40) is arranged on thin-wall regions (31) as Fig. 7 is illustrative.By adopting this structure, be easy to form the reactive chip of surfacing.And because vibration generating unit (40) does not directly contact with sample solution, improved the permanance of chip, also had the influence that when mensuration resonant frequency described later, also can get rid of noise, measured more accurately.
Another kind of form as reactive chip of the present invention, as the planimetric map among Fig. 7 is illustrative, be independently (the 6th invention) for each vibration generating unit from the lead-in wire separately (13) (14) of each vibration generating unit (40) the 1st electrode (11) the 2nd electrode (12) of drawing.Like this, each vibration plane (50) can be with different frequencies or amplitude vibration.Perhaps as so that another kind of form, also can the lead-in wire of any one party of the 1st electrode (11) and the 2nd electrode (12) is shared (the 7th invents).For example, among Fig. 8 that the lead-in wire (13) of the 1st electrode (11) is shared, can simplify the processing of lead-in wire.When the vibration plane more than 4 or 4 is arranged to clathrate, can be shared the contact conductor in the same row vibration plane, the vibration plane that makes these same row is with same amplitude vibration.
The reactive chip of the application's the 8th invention has the unit of the resonant frequency of measuring vibration plane.This resonant frequency is measured relevant principle and concrete grammar etc., the same substantially with the invention (table 99/034176 communique, spy open flat 08-201265 communique again) of the applicant's application before, can be according to table 99/034176, spy open the method formation determination unit of putting down in writing in the flat 08-201265 communique again.Promptly, this resonant frequency, particularly, material is being arranged when the outside is attached to vibration plane, touch the proportion of the sample solution of vibration plane, when viscosity changes, can detect the variation of the resonant frequency of vibration plane by the variation of electric constant that detection comprises the loop of piezoelectric/electrostrictive film element.
With regard to the application's the 9th reactive chip of inventing, the 1st electrode surface is the stationary plane of capture probe, and the 1st electrode and the 2nd electrode have also been connected direct supply except that AC power.That is, this reactive chip removes and can make outside the vibration plane vibration by using AC power to the 1st electrode and the 2nd electrifying electrodes, can also give the direct current of connecting plus or minus as the 1st electrode of capture probe stationary plane.The connection of this DC current can be shown record in the 2001-501301 communique according to the spy.
The 10th invention is a reactive chip of having fixed various different types of capture probes at each vibration plane." variety classes " in this case for example is under the situation of dna fragmentation, refers to various base sequence differences, under the situation of peptide, refers to the amino acid sequence difference.For example, in Fig. 9, on 16 vibration planes, fixed different capture probe A～P.And the reactive chip of the 10th invention can be used in the target substance detection method of the 19th invention.
The method of invention 19 is to detect the detection method of the target substance that combines with capture probe, be characterised in that, under the state of the vibration plane vibration of the reactive chip of described the 10th invention, the test portion that contains the signization target substance is contacted with the capture probe of reactive chip, stop the vibration of vibration plane, as index, detect the target substance that is incorporated into capture probe with sign.
Method of the present invention is characterised in that the target substance in common reactive chip has added the operation of " stationary plane of vibration capture probe " in detecting.That is, by vibration, the interior target substance of sample solution that touches reactive chip spreads to be better than the degree that freely spreads, and consequently, has promoted target substance to combine with the specificity of capture probe.And then, can get rid of or reduce mispairing combination, non-specific adsorption owing under the state that makes the capture probe vibration, hybridize.Like this, can detect them with combining of each self-corresponding capture probe by detecting the different different molecule of dna fragmentation (for example SNPs), spatial structure of single base.
The time interval of the vibration of vibration plane, can come suitable setting according to the kind of capture probe, target substance, for example under the situation of DNA chip, can set 1～32 second for.In addition, the vibration frequency of vibration plane can be set for about 10～1MHz, and amplitude setting is about 0.001～10 μ m.
In the method, the signization of target substance can be used enzyme, radioactive isotope, fluorchrome, fluorescence protein etc. according to this substance classes.As long as it is big that enzyme satisfies turnover number (turnover number), stablize, make conditions such as substrate specificity is painted during with antibodies, just without particular limitation.For example can use peroxidase, beta galactosidase, alkaline phosphatase, glucose oxidase, acetylcholinesterase, glucose-6-phosphate dehydrogenase (G6PD), malic dehydrogenase etc.Also can use enzyme inhibitor matter, coenzyme etc.As matrix, can use known material according to the kind of enzyme.For example, when peroxidase is used as enzyme, use 3,3 ', 5,5 '-tetramethyl benzidine, when alkaline phosphatase is used as enzyme, use p-nitrophenol etc.As radioactive isotope, can use
125I,
3H etc.Can utilize fluorescein isothiocyanate (FITC), TRITC (TRITC) etc. as fluorchrome.In addition, fluorescence protein is a kind of protein that sends fluorescence when shining exciting light, for example the egfp hrGFP in the egfp (GFP) in luminescent jellyfish source and mutant EGFP, EYFP (yellow fluorescence), ECFP (blue-fluorescence), DsRed1 (red fluorescence), DsRed2, sea pansy (Renilla reniformis) source etc.As previously discussed sign material and target substance for example can be by realizing integrated based on combinations such as hydrogen bond, hydrophobic bond, ionic link, coordination bonds.Further, because the polynucleotide sequence of coding fluorescence protein is known, thereby fluorescin qualitative character dna fragmentation, fluorescin qualitative character protein or peptide etc. can easily prepare by known genetic engineering method.
When detection is incorporated into the target substance of capture probe as index with above sign, for example, under the situation of enzyme sign, be added under the enzyme effect and decompose and colorific substrate, try to achieve enzymatic activity by the decomposition amount of optical detecting substrate again, it is converted into the combining target amount, by relatively calculating the object quality with standard value.Use under the radioisotopic situation, utilize scintillation counter to wait and measure the quantity of X-rays X that radioactive isotope sends.Use under the situation of fluorchrome or fluorescence protein, can utilize the determinator that combines by fluorescent microscope to measure fluorescence volume.
The reactive chip of the 11st invention is a kind of form of the reactive chip of described the 10th invention, and is the same with described the 8th invention, is the reactive chip with " unit of measuring the resonant frequency of piezoelectric/electrostrictive film element ".Reactive chip in the 11st invention can be used in the target substance detection method of the 20th invention.
The method of the 20th invention is to detect the method for the target substance that combines with capture probe, it is characterized in that, under the state of the vibration plane that vibrates the described the 11st reactive chip of inventing, the test portion that contains target substance is contacted with the probe of reactive chip, as index, detect target substance with the variation of the resonant frequency of piezoelectric/electrostrictive film element.
That is, this method is, with owing to target-probe and capture probe in conjunction with the variation of the resonant frequency of the vibration plane that produces as index, the method for detection target substance.By this method, target substance need not be identified and just testing result can be obtained.Can also be in real time through the time measure the binding capacity of target substance.Further, can carry out mark to target substance, the same with the method for described the 19th invention, will carry out more high-precision test with the detection combination of sign as index.
Reactive chip in the 11st invention can also be used in the detection method of the 21st target substance of inventing.
The method of the 21st invention is a kind of form of described the 20th invention, be in the vibration plane of vibration reactive chip, make temperature through the time state that changes under, test portion is contacted with probe, with the variation of the resonant frequency of piezoelectric/electrostrictive film element as index, through the time detect the method for target substance.For example, the situation of DNA chip, under the state of vibration vibration plane, with the temperature of hybridization reaction within a certain period of time (for example 10 minutes at interval) change to about 38～98 ℃, detect the Tm (fluxing temperature) that respectively identifies DNA by the quality of measuring in the meantime with the target dna of capture probe DNA hybridization.
The reactive chip of the 12nd invention is the another kind of form of described the 10th invention, and the 1st electrode surface is the stationary plane of capture probe, and the 1st electrode and the 2nd electrode have also been connected direct supply except that AC power.This reactive chip can be used in the detection method of the 22nd target substance of inventing.
The method of the 22nd invention is to detect the method for the target substance that combines with capture probe, it is characterized in that, under the state of the vibration plane vibration that makes the described the 12nd reactive chip of inventing, the test portion that contains the signization target substance and the probe of reactive chip are contacted, after waiting to stop the vibration of vibration plane, give the negative DC current of connecting certain hour as the 1st electrode of the stationary plane of capture probe, as index, detect the target substance that is incorporated into capture probe with sign.This method is that the described the 19th method of inventing and the method combination according to nano chips that is documented in special flat 09-503307 communique of table and the Te Biao 2001-501301 communique are got.In particular for the method that the described the 12nd reactive chip of inventing is used as the DNA chip.By with the vibration of capture probe stationary plane with make that capture probe is electronegative to be made up, can get rid of the mispairing combination of sign DNA and dna probe effectively.
DC current can suitably be selected according to the size of employed solution, vibration plane, the concentration of DNA etc., can connect the electric current 1～180 second, preferred about 10～60 seconds of 0.1～1000 nanoampere, preferred 1～30 nanoampere.
The reactive chip of the 13rd invention is the described the 2nd to the 7th invention and then another kind of form, be that the vibration plane permutation more than 3 or 3 is arranged to same row, or the vibration plane permutation more than 4 or 4 is arranged to the clathrate of n (n is more than or equal to 2) * m (m is more than or equal to 2), and on the vibration plane of same row fixing reactive chip with a kind of capture probe.
At this moment " with a kind of ", for example if dna fragmentation, it is identical then to refer to base sequence; If peptide chain, it is identical then to refer to amino acid sequence.For example, in the example of Figure 10, on 4 vibration planes of the 1st row, fixed identical capture probe (A) separately, listed the 2nd～4 and fixed identical capture probe (B), (C), (D) separately.And the reactive chip of the 13rd invention can be used in the detection method of the 23rd target substance of inventing.
The method of the 23rd invention is to detect the method for plurality of target material to the compatibility of capture probe, it is characterized in that, under the state of each vibration plane with different amplitude vibrations of same row vibration plane of the reactive chip of described the 13rd invention, multiple sign target substance is contacted with the capture probe of reactive chip, stop the vibration of vibration plane, as index, detect the compatibility degree of the target substance of capture probe that be incorporated into sign to various probes.
That is, according to this method, under the state of each vibration plane that makes same row vibration plane with the various amplitude vibration, carry out the hybridization of target substance and capture probe, by to identify as index, detect the object quality that is incorporated into capture probe, can begin to classify successively from the strong material of affinity.In addition, used in the method for the 24th invention of reactive chip of the 14th invention, with the quality measured according to the difference of resonant frequency as index, can carry out through the time classification; In the method for the 25th invention, can measure the hybridization of following temperature variation.Used in the method for the 26th invention of reactive chip of the 15th invention, by with the vibration of capture probe stationary plane with make that capture probe is electronegative makes up, can and then detect the compatibility of sign DNA and dna probe accurately.
The reactive chip of the 16th invention is other forms of another kind of described the 2nd to the 7th invention, be that the vibration plane permutation more than 3 or 3 is arranged to same row or the vibration plane permutation more than 4 or 4 is arranged to the clathrate of n (n is more than or equal to 2) * m (m is more than or equal to 2), and on the vibration plane of same row, fixed the reactive chip of the capture probe that combines with the different parts of target substance separately.At this moment " combining with the different parts of target substance " for example, if dna fragmentation, then refers to the zones of different of its base sequence and combines; If peptide chain, then refer to the zones of different of its full length amino acid sequence and combine.For example in the example of Figure 11, capture probe A1～the A4 in 4 zones in turn that will begin corresponding to an end of chromosomal DNA (A) is fixed on 4 vibration planes of the 1st row, lists the capture probe of fixing separately corresponding to 4 zones of chromosome (B)～(D) the 2nd～4.In addition, for example, in the example of Figure 12, on 4 * 4 clathrate vibration plane, fixed the capture probe of the various combinations in 4 zones in turn that the end corresponding to chromosomal DNA (A) begins separately.
And the reactive chip of the 16th invention can be used in the target substance detection method of the 27th invention.
The method of the 27th invention is to detect the method for target substance variation, it is characterized in that, under the situation of the same row vibration plane vibration that makes the described the 16th reactive chip of inventing, the test portion that contains the signization target substance is contacted with the capture probe of reactive chip, stop the vibration of vibration plane, by to identify as index, detect the target substance that is incorporated into capture probe, detect the variation of target substance.At this moment " variation " refers to disappearance, replacement, insertion, amplification, waits repeatedly.In particular, refer to chromosomal DNA these variations, variation or these the expression product of corresponding mRNA, cDNA are the same variation of protein, peptide etc. with it.
Such as, during according to the formation immobilized capture probes of Figure 11, target substance (chromosomal DNA) is if normal, and then shown in the right side of Figure 11, target substance combines with each probe respectively.But as shown in figure 13, when the binding capacity with probe 3 and 4 became 2 times, amplification had taken place in the 3-4 that can detect corresponding to the chromosomal DNA zone of probe 3 and 4 correspondences.In addition, as shown in figure 14, combine, and when not combining, can detect disappearance corresponding to the chromosomal DNA zone 3 of probe 3 with probe 3 with probe 1,2,4.
And then, by formation immobilized capture probes, for example can detect insertion, replacement of chromosomal DNA etc. with Figure 12.For example shown in the hurdle, Figure 15 left side, target substance (chromosomal DNA) and the independent probe of A1～A4, and A1+2 and A3+4 probe when combining shown in hurdle, Figure 15 right side, can detect between the zone 2 and 3 of chromosomal DNA and insert the X arrangement.In addition, shown in hurdle, Figure 16 left side, the independent probe of chromosomal DNA and A1～A4, A1+2, A2+4, A3+4, the A1+2+4 probe in conjunction with the time, shown in the right hurdle of Figure 16, can detect the replacement of chromosomal DNA regional 3 and 4.
In addition, in the method for the 28th invention of the reactive chip that has used the 17th invention, as index, can detect the variation of target substance with the quality measured according to the difference of resonant frequency.For example, in the example of Figure 13, the quality of measuring is 6/4 times, and the quality of measuring in the example of Figure 14 is 3/4 times.Used in the method for the 29th invention of reactive chip of the 18th invention,, can detect the variation among the sign DNA more accurately by with the vibration of capture probe stationary plane with make the electronegative combination of capture probe.
Certainly, the application's invention is not limited to above example, particularly also has various forms.
Utilize possibility on the industry
Such as above detailed description, according to the application's invention, but can provide Reaction time shorten, and And effectively prevent the mispairing combination, but high accuracy detects the widely new reactive chip of target substance. Also The method of using this reactive chip to detect target substance is provided. By this detection method, in the past The reactive chip detection to the small difference of target substance that can't realize also be achieved.
Claims (5)
1. the detection method of a target substance, it is to detect the method for plurality of target material to the compatibility of capture probe, it is characterized in that, under the state of each vibration plane with different amplitude vibrations of the same row vibration plane that makes following reactive chip, multiple sign target substance is contacted with the capture probe of reactive chip, stop the vibration of vibration plane, as index, detect the compatibility degree of the target substance of capture probe that be incorporated into each capture probe with sign; Described reactive chip has been arranged the vibration plane more than 3 or 3 in permutation on the substrate, and on each vibration plane, fixed the capture probe that combines with target substance, wherein, substrate has thin-wall regions and the thick wall area around it, and thin-wall regions is a vibration plane; Each vibration plane has the vibration generating unit that the insertion piezoelectric/electrostrictive film element forms between the 1st electrode and the 2nd electrode respectively; Vibration plane permutation more than 3 or 3 is arranged to same row or the vibration plane permutation more than 4 or 4 is arranged to the clathrate of n * m, and fix the capture probe of same kind on the vibration plane of same row, wherein, n is more than or equal to 2, and m is more than or equal to 2.
2. detection method according to claim 1 is characterized in that, when making vibration plane vibration, make temperature through the time state that changes under, test portion is contacted with capture probe.
3. the detection method of a target substance, it is to detect the method for plurality of target material to the compatibility of capture probe, it is characterized in that, make under the state of same row vibration plane with different amplitude vibrations of following reactive chip, target substance is contacted with the capture probe of reactive chip, as index, detect the compatibility degree of the target substance of capture probe that be incorporated into the variation of the resonant frequency of vibration plane to each capture probe; Described reactive chip has been arranged the vibration plane more than 3 or 3 in permutation on the substrate, and on each vibration plane, fixed the capture probe that combines with target substance, wherein, substrate has thin-wall regions and the thick wall area around it, and thin-wall regions is a vibration plane; Each vibration plane has the vibration generating unit that the insertion piezoelectric/electrostrictive film element forms between the 1st electrode and the 2nd electrode respectively; Vibration plane permutation more than 3 or 3 is arranged to same row or the vibration plane permutation more than 4 or 4 is arranged to the clathrate of n * m, and fix the capture probe of same kind on the vibration plane of same row, wherein, n is more than or equal to 2, and m is more than or equal to 2; Described reactive chip has the unit of measuring the vibration plane resonant frequency.
4. detection method according to claim 3, it is characterized in that, in the vibration plane vibration that makes reactive chip, make temperature through the time state that changes under, test portion is contacted with capture probe, with the variation of the resonant frequency of vibration plane as index, through the time detect having or not of target substance.
5. the detection method of a target substance, it is to detect the method for plurality of target material to the compatibility of capture probe, it is characterized in that, under the state of each vibration plane with different amplitude vibrations of the same row vibration plane that makes following reactive chip, various sign target substances are contacted with the capture probe of reactive chip, after the vibration that stops vibration plane, give the negative DC current of connecting certain hour as the 1st electrode of the stationary plane of capture probe, as index, detect the compatibility degree of the target substance of capture probe that be incorporated into sign at each capture probe; Described reactive chip has been arranged the vibration plane more than 3 or 3 in permutation on the substrate, and on each vibration plane, fixed the capture probe that combines with target substance, wherein, substrate has thin-wall regions and the thick wall area around it, and thin-wall regions is a vibration plane; Each vibration plane has the vibration generating unit that the insertion piezoelectric/electrostrictive film element forms between the 1st electrode and the 2nd electrode respectively; Vibration plane permutation more than 3 or 3 is arranged to same row or the vibration plane permutation more than 4 or 4 is arranged to the clathrate of n * m, and fix the capture probe of same kind on the vibration plane of same row, wherein, n is more than or equal to 2, and m is more than or equal to 2; The 1st electrode surface of described reactive chip is the capture probe stationary plane, and the 1st electrode and the 2nd electrode and then have also connected direct supply except that AC power.
Applications Claiming Priority (2)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| JP001577/2003 | 2003-01-07 | ||
| JP2003001577A JP3920223B2 (en) | 2003-01-07 | 2003-01-07 | Reactive chip and target substance binding detection method using this chip |
Publications (2)
| Publication Number | Publication Date |
|---|---|
| CN1723392A CN1723392A (en) | 2006-01-18 |
| CN100478688C true CN100478688C (en) | 2009-04-15 |
Family
ID=32708823
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CNB2004800019163A Expired - Fee Related CN100478688C (en) | 2003-01-07 | 2004-01-07 | Reactive chip and method for detecting bond of target substance using that chip |
Country Status (6)
| Country | Link |
|---|---|
| US (2) | US20040197806A1 (en) |
| EP (1) | EP1589340B1 (en) |
| JP (1) | JP3920223B2 (en) |
| CN (1) | CN100478688C (en) |
| DE (1) | DE602004024957D1 (en) |
| WO (1) | WO2004061451A1 (en) |
Families Citing this family (12)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR100631208B1 (en) * | 2004-07-20 | 2006-10-04 | 삼성전자주식회사 | Apparatus for detecting bio-bonding using electromagnetic and detecting method using the same |
| EP1846760B1 (en) * | 2005-01-27 | 2010-12-15 | Quest Diagnostics Investments Incorporated | Rapid comparative genome hybridization |
| JP2007057467A (en) * | 2005-08-26 | 2007-03-08 | Matsushita Electric Ind Co Ltd | Specimen reactor and target molecule detector |
| EP2053400A1 (en) * | 2007-10-22 | 2009-04-29 | Consejo Superior De Investigaciones Cientificas | Method and system for detection of a selected type of molecules in a sample |
| DE102008052437A1 (en) | 2008-10-21 | 2010-04-29 | Siemens Aktiengesellschaft | Device and method for detecting a substance with the aid of a thin-film resonator with an insulating layer |
| CN102074648B (en) * | 2009-11-24 | 2015-04-15 | 清华大学 | Piezoelectric element and preparation method thereof |
| TWI407607B (en) * | 2010-01-22 | 2013-09-01 | Hon Hai Prec Ind Co Ltd | Piezoelectric element and method for making the same |
| JP6213924B2 (en) * | 2012-08-30 | 2017-10-18 | 学校法人神奈川大学 | Nucleic acid denaturing apparatus, nucleic acid denaturing method, and nucleic acid amplification method |
| JP2015072153A (en) * | 2013-10-02 | 2015-04-16 | 神奈川県 | Biosensor and method for manufacturing the same |
| KR101780808B1 (en) | 2016-06-29 | 2017-09-21 | 주식회사 스몰머신즈 | Membrane type resonant sensor |
| US20190302137A1 (en) * | 2018-03-29 | 2019-10-03 | Eiken Kagaku Kabushiki Kaisha | Automatic genetic testing device |
| TWI818596B (en) * | 2022-06-22 | 2023-10-11 | 嘉碩生醫電子股份有限公司 | Shear-mode liquid-phase sensor having groove structure and methods of manufacturing and using the same |
Family Cites Families (19)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| EP0215669A3 (en) * | 1985-09-17 | 1989-08-30 | Seiko Instruments Inc. | Analytical device and method for analysis of biochemicals, microbes and cells |
| EP0494896B1 (en) * | 1989-10-04 | 1994-07-06 | E.I. Du Pont De Nemours And Company | Assay method for biological target complexes on the surface of a biosensor |
| US5478756A (en) * | 1990-07-24 | 1995-12-26 | Fisons Plc | Chemical sensor for detecting binding reactions |
| US5474796A (en) * | 1991-09-04 | 1995-12-12 | Protogene Laboratories, Inc. | Method and apparatus for conducting an array of chemical reactions on a support surface |
| US5605662A (en) * | 1993-11-01 | 1997-02-25 | Nanogen, Inc. | Active programmable electronic devices for molecular biological analysis and diagnostics |
| US5846708A (en) * | 1991-11-19 | 1998-12-08 | Massachusetts Institiute Of Technology | Optical and electrical methods and apparatus for molecule detection |
| JP3425193B2 (en) * | 1993-09-07 | 2003-07-07 | テルモ株式会社 | Gene sensor and gene detection method using the same |
| US6686151B1 (en) * | 1998-02-06 | 2004-02-03 | Digene Corporation | Immunological detection of RNA:DNA hybrids on microarrays |
| JP3545269B2 (en) * | 1998-09-04 | 2004-07-21 | 日本碍子株式会社 | Mass sensor and mass detection method |
| JP3876082B2 (en) * | 1998-10-29 | 2007-01-31 | 株式会社日立製作所 | Manufacturing method of two-dimensional array type module |
| US6518690B2 (en) * | 2000-04-19 | 2003-02-11 | Ngk Insulators, Ltd. | Piezoelectric/electrostrictive film type elements and process for producing the same |
| JP3757329B2 (en) * | 2000-08-07 | 2006-03-22 | 株式会社日立製作所 | Hazardous chemical substance monitoring apparatus and method |
| AU2001292884A1 (en) * | 2000-09-20 | 2002-04-02 | Molecular Reflections | Microfabricated ultrasound array for use as resonant sensors |
| US7223363B2 (en) * | 2001-03-09 | 2007-05-29 | Biomicro Systems, Inc. | Method and system for microfluidic interfacing to arrays |
| US20030124717A1 (en) * | 2001-11-26 | 2003-07-03 | Yuji Awano | Method of manufacturing carbon cylindrical structures and biopolymer detection device |
| US7181977B2 (en) * | 2002-01-22 | 2007-02-27 | Measurement Specialties, Inc. | Sensor assembly with lead attachment |
| JP2003307481A (en) * | 2002-04-17 | 2003-10-31 | Canon Inc | Multichannel biosensor |
| US7067961B2 (en) * | 2002-07-12 | 2006-06-27 | Ngk Insulators, Ltd. | Piezoelectric/electrostrictive film device, and manufacturing method of the device |
| EP1546396A4 (en) * | 2002-10-02 | 2006-10-18 | New Light Ind Ltd | Manufacturing method and readout system for biopolymer arrays |
-
2003
- 2003-01-07 JP JP2003001577A patent/JP3920223B2/en not_active Expired - Fee Related
-
2004
- 2004-01-06 US US10/751,517 patent/US20040197806A1/en not_active Abandoned
- 2004-01-07 EP EP04700535A patent/EP1589340B1/en not_active Expired - Fee Related
- 2004-01-07 CN CNB2004800019163A patent/CN100478688C/en not_active Expired - Fee Related
- 2004-01-07 DE DE602004024957T patent/DE602004024957D1/en not_active Expired - Lifetime
- 2004-01-07 WO PCT/JP2004/000038 patent/WO2004061451A1/en active Application Filing
-
2008
- 2008-07-16 US US12/219,126 patent/US20080287313A1/en not_active Abandoned
Non-Patent Citations (2)
| Title |
|---|
| 特开平7－75598A 1995.03.20 |
| 特表2001-501301A 2001.01.30 |
Also Published As
| Publication number | Publication date |
|---|---|
| DE602004024957D1 (en) | 2010-02-25 |
| CN1723392A (en) | 2006-01-18 |
| US20080287313A1 (en) | 2008-11-20 |
| EP1589340A1 (en) | 2005-10-26 |
| JP3920223B2 (en) | 2007-05-30 |
| EP1589340A4 (en) | 2007-06-13 |
| JP2004264023A (en) | 2004-09-24 |
| EP1589340B1 (en) | 2010-01-06 |
| WO2004061451A1 (en) | 2004-07-22 |
| US20040197806A1 (en) | 2004-10-07 |
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| Tang et al. | Fabrication of immunosensor microwell arrays from gold compact discs for detection of cancer biomarker proteins | |
| US8420313B2 (en) | Multiplexed electrochemical detection system and method | |
| US20080287313A1 (en) | Reactive chips and methods for detecting bindings of target substances utilizing the chips | |
| US7892414B1 (en) | Electrochemical biosensors, applications and methods of making biosensors | |
| Kusnezow et al. | Antibody microarrays: the crucial impact of mass transport on assay kinetics and sensitivity | |
| CN101126734A (en) | Biosensor based on aptamer modified conducting polymer and its preparation method and uses | |
| WO2005095262A1 (en) | Microchip and method for detecting molecules and molecular interactions | |
| WO2018014719A1 (en) | Detection electrode structure, detection aperture plate, and prefabricated detection aperture plate | |
| EP2324353B1 (en) | Selectively functionalized transducer microarray | |
| JP2004132954A (en) | Method and detector for detecting one or plurality of analytes, and use of detector | |
| Díaz‐González et al. | Diagnostics using multiplexed electrochemical readout devices | |
| Henry et al. | Design and testing of a packaged microfluidic cell for the multiplexed electrochemical detection of cancer markers | |
| US20230031265A1 (en) | Devices, methods and compositions for aptamer screening | |
| US20050037407A1 (en) | Methods and apparatuses for electronic determination of analytes | |
| EP1964933A1 (en) | Electrochemical sensor, kit comprising said sensor and process for the production thereof | |
| US20090019934A1 (en) | Micro-sensor for sensing chemical substance | |
| KR101729489B1 (en) | Biosensor utilizing conductive particles and the combination of polynucleotides corresponding to conductive particles, and method for detecting electric signal using the same | |
| CN1129669C (en) | In-situ biochip and its preparing process | |
| JP2005037376A (en) | Method and device for quantitative electrical detection for analyte | |
| KR100994752B1 (en) | Direct Electrical Detection Method of DNA-Hybridization and chip Fabrication | |
| JP2005091246A (en) | Device and its manufacturing method |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| C06 | Publication | ||
| PB01 | Publication | ||
| C10 | Entry into substantive examination | ||
| SE01 | Entry into force of request for substantive examination | ||
| C14 | Grant of patent or utility model | ||
| GR01 | Patent grant | ||
| C17 | Cessation of patent right | ||
| CF01 | Termination of patent right due to non-payment of annual fee |
Granted publication date: 20090415 Termination date: 20110107 |